Use of diuretics for treating swellings

ABSTRACT

The present invention relates to the use of a diuretic, especially a loop diuretic, for the treatment of local skin swellings. The invention further relates to pharmaceutical preparations of diuretics in topical form.

The present invention relates to topical preparations containingdiuretics, especially loop diuretics, and to their use for the treatmentof local skin swellings.

Diuretics are understood as meaning substances which cause an increasedexcretion of water and salt. Their field of use covers both thetreatment of kidney diseases and the treatment of arterial hypertonia,cardiac insufficiency and the mobilization of general or organicoedemas. Diuretics are subdivided into different groups according totheir principle of action, said groups including osmotic diuretics,carboanhydrase inhibitors, thiazide diuretics, loop diuretics, potassiumsparing diuretics and aldosterone antagonists.

Loop diuretics are used particularly in the treatment of organic oedemas(especially of cardiac, renal or hepatic origin) and asantihypertensives. They are characterized by an inhibitory effect on thereabsorption of chloride and sodium in the ascending limb of Henle'sloop and are also effective in cases of reduced glomerular filtrationrate. One of the most prominent representatives of loop diuretics isfurosemide, the group also including azosemide, bumetanide, piretanideand torasemide. Loop diuretics are administered orally or intravenouslyand are used in both short-term and long-term therapies. EP 0 247 507describes a transdermic therapeutic system for loop diuretics whichproduces a retarded systemic action via percutaneous absorption.

It has now been found, surprisingly, that topical pharmaceuticalpreparations of diuretics, especially loop diuretics, are suitable forthe local treatment of skin swellings. Their effect can even markedlyexceed that of the intravenous infusion of loop diuretics, or they canfacilitate the action of previously inactive intravenous infusions ofloop diuretics. This makes it possible to treat local oedemas whichpreviously could only be treated inadequately by manual drainage.

The invention therefore relates to the use of a diuretic, especially aloop diuretic, or a pharmaceutically acceptable salt thereof for themanufacture of a topical pharmaceutical preparation for the treatment oflocal skin swellings, and to the topical preparations themselves.

Within the framework of the present invention, skin swellings includeparticularly oedematous swellings or swellings caused by a venous orlymphatic inflammation.

Within the framework of the present invention, it is possible inprinciple to use any of the types of diuretic mentioned above. Theseinclude e.g. thiazide diuretics, such as hydrochlorothiazide(6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide1,1-dioxide) and ethacrynic acid([2,3-dichloro-4-(2-ethylacryloyl)phenoxy]acetic acid), carboanhydraseinhibitors, such as acetazolamide(5-acetylamino-1,3,4-thiadiazole-2-sulfonamide), potassium sparingdiuretics, such as triamterene (2,4,7-triamino-6-phenylpteridine), andespecially loop diuretics.

The loop diuretics which can be used within the framework of the presentinvention include furosemide (4-chloro-N-furfuryl-5-sulfamoylanthranilicacid), azosemide (2-chloro-5-(1H-tetrazol-5-yl)-2-thienylsulfanilamide),bumetanide (3-butylamino-4-phenoxy-5-sulfamoylbenzoic acid), piretanide(4-phenoxy-3-(1-pyrrolidinyl)-5-sulfamoylbenzoic acid) and torasemide(1-isopropyl-3-[(4-toluidino-3-pyridyl)sulfonyl]urea). It is preferableto use furosemide, piretanide and torasemide and very particularlypreferable to use furosemide. Pharmaceutical preparations of theseactive substances in tablet form or as substances in tablet form or asinjection solutions are commercially available.

Possible pharmaceutically acceptable salts are both water-soluble andsparingly water-soluble salts that are generally known to those skilledin the art. The topical preparations according to the invention, whichcontain one or more diuretics, especially loop diuretics, as activesubstances and are suitable for application to the skin, includeointments, pastes, lotions, creams, gels and tinctures. Within theframework of the present invention, tinctures include liquidpreparations containing active substances which are suitable forapplication to the skin but are not intended for oral or intravenousadministration.

The preparations are manufactured in known manner using the known andconventional pharmaceutical auxiliary substances and other conventionalexcipients and diluents (List et al., Arzneiformenlehre, Wiss.Verlagsges., Stuttgart, 1985; Sucka et al., Pharmazeutische Technologie,Thieme Verlag, Stuttgart, 1978).

In the manufacture of an ointment, for example, it is possible to useorganogels (e.g. Vaseline, Plastibase), lipogels (e.g. beeswax),hydrogels (e.g. Aerosil®, bentonite, starch derivatives, polyacrylicacid, polyethylene glycols) or silicone gels as the ointment base. Apreferred ointment base is Vaseline, it also being possible for theointment to contain other materials such as fatty alcohols, glycerylmonostearates, triglycerides, alkylene glycols, dimethyl sulfoxide andwater. A very particularly preferred ointment base is the DAC base cream(Cremor basalis, Deutscher Arzneimittel-Codex), which contains whiteVaseline, glycerol monostearate 60, cetyl alcohol, medium-chaintriglycerides, macrogol 1000 glycerol monostearate, propylene glycol andwater.

Creams can be manufactured using the above-mentioned ointment bases incombination with larger amounts of water and also, in particular, fatsand oils, waxes, fatty acids and fatty acid esters, long-chain alcoholsand emulsifiers.

The preparations in gel form include organogels (i.e. hydrocarbon gels,e.g. Vaseline, Plastibase), lipogels (e.g. natural fats, beeswax),hydrogels (e.g. hydroxypropyl cellulose, hydroxypropyl methyl cellulose,Aerosil®, bentonite, starch derivatives, polyacrylic acid, polyethyleneglycols), silicone gels or emulsion gels containing conventionalemulsifiers, as well as oleogels composed essentially of liquid paraffinwith polyethylene or oils and thickeners.

It is further possible to add preservatives, stabilizers, buffersubstances, colourants, antioxidants, etc.

Tinctures for topical application to the skin can be manufactured usinge.g. water or physiologically acceptable solvents like alcohols(ethanol, propylene glycol or polyglycols), oils or paraffins.

The pharmaceutical topical preparations according to the inventioncontain the diuretic or a pharmaceutically acceptable salt thereof in anamount of 0.1 to 10 wt. %, based on the pharmaceutical preparation. Theactive substance content is preferably in the range from 0.1 to 1 wt. %and very particularly preferably 0.2 wt. %.

To introduce the diuretics into the topical preparations according tothe invention, it is possible to use commercially available activesubstance formulations, for example solutions in ampoule form. Variousfurosemide solutions are obtainable e.g. from Hoechst (Lasix®), CT(Furo®), Ratiopharm (Furosemid-Ratiopharm®) and Hexal (Furorese®).

In a preferred embodiment, the pharmaceutical preparation is in the formof an ointment containing furosemide or a pharmaceutically acceptablesalt thereof in an amount of 0.2 wt. %, based on the pharmaceuticalpreparation.

Without intentionally implying a restriction to one particular theory inorder to explain the ascertainable action of diuretics, especially loopdiuretics, the mechanisms of action illustrated below are considered.

Obstruction of the venous and lymphatic discharge, and the resultingreflux in both vascular systems, are described as major factors of thelocal oedema.

Loop diuretics inhibit Na+K+Cl cotransporters. There are at least sixdifferent isoforms of absorbing cotransporters. A cotransporter, namelya secretory cotransporter, was first isolated from an anal gland of theshark. Whereas the “absorbing” cotransporter seems to be expressed onlyin the kidney, secretory cotransporters are expressed in many tissues.The local effect of furosemide could therefore involve a blockade of asecretory cotransporter.

Recently, however, many results have come to light which have qualifiedvarious tissues as having a “single” specialized function. It has beenshown that immune cells produce neurotrophins and pituitary hormoneswhose production had long been ascribed only to brain cells. Aninvariant chain of the T cell receptor has recently been discovered onbrain cells. Thus it seems that a receptor or a gene product is firstdiscovered in the tissue with the highest expression, i.e. at the siteof most intense utilization, but other tissues are capable of performingthe same tasks at a lower level with the same molecules.

However, yet another important effect of loop diuretics is known whichcannot be explained by the “classic” accumulation at the Cl binding siteof the cotransporter protein in the ascending limb of Henle's loop:

Loop diuretics increase the venous absorption capacity (vasodilatoryeffect). The mode of action is not known. The profound action of loopdiuretics on pulmonary oedema starts before diuresis and is attributedto the increase in venous absorption capacity.

Thus the local mode of action could be connected with an inhibition ofthe secretory cotransporter and/or a vasodilatory effect. However, loopdiuretics are also capable of inhibiting Na+K+ATPase, glycolysis,mitochondrial respiration, the microsomal Ca²⁺ pump, adenylcyclase,phosphodiesterase and prostaglandin dehydrogenase. These inhibitoryeffects on electrolyte transport, previously observed only in vitro,could be observed in many tissues only at high concentrations. Theapplication of an ointment might be capable of achieving such highconcentrations locally.

The pharmaceutical preparation in topical form is applied to theaffected areas of skin several times a day and as a rule twice to fourtimes a day. The frequency of application can be adapted as required.The local treatment of a swelling with the preparation according to theinvention can be administered together with a medicinal treatmentappropriate for the disease.

The invention is illustrated in greater detail below with the aid ofExamples.

Preparation of a Furosemide Ointment

The DAC base cream (Cremor basalis, Deutsche Arzneimittel-Codex) havingthe following composition was used as the ointment base: per 100 g offormulation: Glycerol monostearate 60  4.0 g Cetyl alcohol  6.0 gMedium-chain triglycerides  7.5 g White Vaseline 25.5 g Macrogol 1000glycerol monostearate  7.0 g Propylene glycol 10.0 g Water   40 g

The ointment was prepared using 68 g of DAC base cream, 12 g of dimethylsulfoxide and 200 mg of furosemide (20 ml of Lasix®, active substanceconcentration 10 mg/ml).

Patient Studies

The local application of furosemide ointment (from the above Example) ona cancer patient with swelling of the genitals after leukocyte apheresisled to a marked regression of the swelling within a few hours. Thiseffect could not be achieved by a previous intravenous administration offurosemide in combination with spironolactone, which is clear evidenceof the local action of furosemide ointment. Furosemide in ointment formis only effective locally, not systemically, with the result that thereis no interference with the patients' electrolyte metabolism.

Treatment of a so-called lymph arm in a breast cancer patient withfurosemide ointment (from the above Example) led to a marked reductionin the oedema after a few applications, making it unnecessary to carryout a lymph drainage.

In another female patient, an armpit swelling attributable to a venousinflammation could be markedly reduced within 12 hours by the localapplication of furosemide ointment (from the above Example).

The furosemide-containing ointment according to the invention led withina short time to a marked regression of swellings of very different typesand thus opens up novel and efficient approaches to the treatment ofswellings.

1-22. (canceled)
 23. A pharmaceutical composition in topical form forthe treatment of local skin swellings comprising an effective amount ofa diuretic or pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier therefore.
 24. The pharmaceuticalcomposition according to claim 23, wherein the diuretic is a loopdiuretic.
 25. The pharmaceutical composition according to claim 23,wherein the loop diuretic is furosemide, azosemide, bumetanide,piretanide or torasemide or a pharmaceutically acceptable salt thereof.26. The pharmaceutical composition according to claim 25, wherein theloop diuretic is furosemide or a pharmaceutically acceptable saltthereof.
 27. The pharmaceutical composition according to claim 23,wherein the pharmaceutical composition comprises a diuretic or apharmaceutically acceptable salt thereof in an amount of 0.1 to 10 wt.%, based on the pharmaceutical preparation.
 28. The pharmaceuticalcomposition according to claim 27, wherein the pharmaceuticalcomposition comprises a diuretic or a pharmaceutically acceptable saltthereof in an amount of 0.2 wt. %, based on the pharmaceuticalpreparation.
 29. The pharmaceutical composition according to claim 23,wherein the pharmaceutical topical composition is in the form of anointment, paste, lotion, cream, tincture or gel.
 30. The pharmaceuticalcomposition according to claim 23, wherein the pharmaceuticalcomposition comprises conventional pharmaceutical auxiliary substances,excipients and/or diluents.
 31. The pharmaceutical composition accordingto claim 23, wherein the pharmaceutical composition is applied locallyto the affected areas of skin 2-4 times a day.
 32. The pharmaceuticalcomposition according to claim 23, wherein the pharmaceuticalcomposition further comprises another medicinal treatment appropriatefor the disease.
 33. A method for the treatment of local skin swellingscaused by venous or lymphatic inflammation comprising topically applyinga diuretic or a pharmaceutically acceptable salt thereof to a patient inneed of such treatment.
 34. The method according to claim 33, whereinthe diuretic is a loop diuretic.
 35. The method according to claim 33,wherein the loop diuretic is furosemide, azosemide, bumetanide,piretanide or torasemide or a pharmaceutically acceptable salt thereof.36. The method according to claim 35, wherein the loop diuretic isfurosemide or a pharmaceutically acceptable salt thereof.
 37. The methodaccording to claim 33, wherein the pharmaceutical composition comprisesa diuretic or a pharmaceutically acceptable salt thereof in an amount of0.1 to 10 wt. %, based on the pharmaceutical preparation.
 38. The methodaccording to claim 37, wherein the pharmaceutical composition comprisesa diuretic or a pharmaceutically acceptable salt thereof in an amount of0.2 wt. %, based on the pharmaceutical preparation.
 39. The methodaccording to claim 33, wherein the pharmaceutical topical composition isin the form of an ointment, paste, lotion, cream, tincture or gel. 40.The method according to claim 33, wherein the pharmaceutical compositioncomprises conventional pharmaceutical auxiliary substances, excipientsand/or diluents.
 41. The method according to claim 33, wherein thepharmaceutical composition is applied locally to the affected areas ofskin 2-4 times a day.
 42. The method according to claim 33, wherein thepharmaceutical composition further comprises another medicinal treatmentappropriate for the disease.